rs2077606

Positions:

• chr17-45451927-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014798.3(PLEKHM1):​c.2498-1164C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 152,308 control chromosomes in the GnomAD database, including 1,584 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1584 hom., cov: 29)
• Consequence: PLEKHM1 NM_014798.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250

Genes affected

PLEKHM1 (HGNC:29017): (pleckstrin homology and RUN domain containing M1) The protein encoded by this gene is essential for bone resorption, and may play a critical role in vesicular transport in the osteoclast. Mutations in this gene are associated with autosomal recessive osteopetrosis type 6 (OPTB6). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]

PLEKHM1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHM1	NM_014798.3	c.2498-1164C>T		intron_variant		ENST00000430334.8	NP_055613.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHM1	ENST00000430334.8	c.2498-1164C>T		intron_variant		1	NM_014798.3	ENSP00000389913.3

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19441 AN: 152190 Hom.: 1586 Cov.: 29

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.128 AC: 19437 AN: 152308 Hom.: 1584 Cov.: 29 AF XY: 0.120 AC XY: 8920 AN XY: 74482

Gnomad4 AFR AF: 0.0597

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0598

Gnomad4 FIN AF: 0.0415

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.171

Alfa AF: 0.158 Hom.: 511

Bravo AF: 0.136

Asia WGS AF: 0.0270 AC: 94 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2077606; hg19: chr17-43529293;